A stabilizing factor for mitochondrial respiratory supercomplex assembly regulates energy metabolism in muscle

Ikeda, Kazuhiro; Shiba, Sachiko; Horie‐Inoue, Kuniko; Shimokata, Kunitoshi; Inoue, Satoshi

doi:10.1038/ncomms3147

Cited by 138 publications

(144 citation statements)

References 52 publications

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“…This may have been due to a different RCC assembly in the so-called supercomplexes. Supercomplex assembling is required for RCC stability and functionality by organizing electron flux and ameliorating the use of available substrates (23,27,56). A more efficient supercomplex assembly might explain the increase in respiratory capacity of IUGR cells.…”

Section: Discussionmentioning

confidence: 99%

Placental mitochondrial content and function in intrauterine growth restriction and preeclampsia

Mandò

Palma

Stampalija

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

164

132

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Intrauterine growth restriction (IUGR) and pregnancy hypertensive disorders such as preeclampsia (PE) associated with IUGR share a common placental phenotype called “placental insufficiency”, originating in early gestation when high availability of energy is required. Here, we assess mitochondrial content and the expression and activity of respiratory chain complexes (RCC) in placental cells of these pathologies. We measured mitochondrial (mt)DNA and nuclear respiratory factor 1 ( NRF1) expression in placental tissue and cytotrophoblast cells, gene and protein expressions of RCC (real-time PCR and Western blotting) and their oxygen consumption, using the innovative technique of high-resolution respirometry. We analyzed eight IUGR, six PE, and eight uncomplicated human pregnancies delivered by elective cesarean section. We found lower mRNA levels of complex II, III, and IV in IUGR cytotrophoblast cells but no differences at the protein level, suggesting a posttranscriptional compensatory regulation. mtDNA was increased in IUGR placentas. Both mtDNA and NRF1 expression were instead significantly lower in their isolated cytotrophoblast cells. Finally, cytotrophoblast RCC activity was significantly increased in placentas of IUGR fetuses. No significant differences were found in PE placentas. This study provides genuine new data into the complex physiology of placental oxygenation in IUGR fetuses. The higher mitochondrial content in IUGR placental tissue is reversed in cytotrophoblast cells, which instead present higher mitochondrial functionality. This suggests different mitochondrial content and activity depending on the placental cell lineage. Increased placental oxygen consumption might represent a limiting step in fetal growth restriction, preventing adequate oxygen delivery to the fetus.

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Section: Discussionmentioning

confidence: 99%

Placental mitochondrial content and function in intrauterine growth restriction and preeclampsia

Mandò

Palma

Stampalija

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

164

132

View full text Add to dashboard Cite

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“…Moreover, previous reports have also shown cell type-dependent effects of RSC disruption on mitochondrial respiration. For instance, SCAFI deficiency causes significantly reduced mitochondrial respiration in MEFs (Ikeda et al, 2013), but only has a mild effect in 143B cells (Pérez-Pérez et al, 2016), and even enhanced the respiration in isolated liver mitochondria (Lapuente-Brun et al, 2013). In T cells, impairing RSCs through SLP2 knockout increased uncoupled respiration but did not alter the basal respiration (Mitsopoulos et al, 2015).…”

Section: Regulation Of Mitoflash Activity By Rsc Formationmentioning

confidence: 99%

Deficiency of PHB complex impairs respiratory supercomplex formation and activates mitochondrial flashes

Jian

Hou

et al. 2017

Journal of Cell Science

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Prohibitins (PHBs; prohibitin 1, PHB1 or PHB, and prohibitin 2, PHB2) are evolutionarily conserved and ubiquitously expressed mitochondrial proteins. PHBs form multimeric ring complexes acting as scaffolds in the inner mitochondrial membrane. Mitochondrial flashes (mitoflashes) are newly discovered mitochondrial signaling events that reflect electrical and chemical excitations of the organelle. Here, we investigate the possible roles of PHBs in the regulation of mitoflash signaling. Downregulation of PHBs increases mitoflash frequency by up to 5.4-fold due to elevated basal reactive oxygen species (ROS) production in the mitochondria. Mechanistically, PHB deficiency impairs the formation of mitochondrial respiratory supercomplexes (RSCs) without altering the abundance of individual respiratory complex subunits. These impairments induced by PHB deficiency are effectively rescued by co-expression of PHB1 and PHB2, indicating that the multimeric PHB complex acts as the functional unit. Furthermore, downregulating other RSC assembly factors, including SCAFI (also known as COX7A2L), RCF1a (HIGD1A), RCF1b (HIGD2A), UQCC3 and SLP2 (STOML2), all activate mitoflashes through elevating mitochondrial ROS production. Our findings identify the PHB complex as a new regulator of RSC formation and mitoflash signaling, and delineate a general relationship among RSC formation, basal ROS production and mitoflash biogenesis.

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“…Furthermore, specific proteins have been found to mediate interactions between specific pairs of respiratory complexes, and functionally removing these proteins prevents the relevant supercomplexes from forming (11)(12)(13)(14). Thus, structural associations between membrane-bound respiratory complexes are increasingly accepted.…”

mentioning

confidence: 99%

Kinetic evidence against partitioning of the ubiquinone pool and the catalytic relevance of respiratory-chain supercomplexes

Blaza

Serreli

Jones

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

163

135

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In mitochondria, four respiratory-chain complexes drive oxidative phosphorylation by sustaining a proton-motive force across the inner membrane that is used to synthesize ATP. The question of how the densely packed proteins of the inner membrane are organized to optimize structure and function has returned to prominence with the characterization of respiratory-chain supercomplexes. Supercomplexes are increasingly accepted structural entities, but their functional and catalytic advantages are disputed. Notably, substrate "channeling" between the enzymes in supercomplexes has been proposed to confer a kinetic advantage, relative to the rate provided by a freely accessible, common substrate pool. Here, we focus on the mitochondrial ubiquinone/ubiquinol pool. We formulate and test three conceptually simple predictions of the behavior of the mammalian respiratory chain that depend on whether channeling in supercomplexes is kinetically important, and on whether the ubiquinone pool is partitioned between pathways. Our spectroscopic and kinetic experiments demonstrate how the metabolic pathways for NADH and succinate oxidation communicate and catalyze via a single, universally accessible ubiquinone/ubiquinol pool that is not partitioned or channeled. We reevaluate the major piece of contrary evidence from flux control analysis and find that the conclusion of substrate channeling arises from the particular behavior of a single inhibitor; we explain why different inhibitors behave differently and show that a robust flux control analysis provides no evidence for channeling. Finally, we discuss how the formation of respiratory-chain supercomplexes may confer alternative advantages on energy-converting membranes.supercomplex | respirasome | mitochondria | respiratory chain | ubiquinone C ontemporary models for the organization of respiratorychain complexes in energy-transducing membranes range from the fluid model to the respirasome model. In the fluid model each complex is a free and independent entity, and substrates exchange freely between enzymes through common ubiquinone/ubiquinol (Q) and cytochrome c ox /c red (cyt c) pools (1-3). In the respirasome model the complexes are assembled into units that contain everything required for catalysis; substrates are channeled between enzymes within the respirasome, not exchanged with external pools (4, 5). Intermediate models, in which some enzymes are free and some assembled into multienzyme supercomplexes, or in which supercomplexes are assembled and disassembled in response to changing conditions, are increasingly considered a realistic combination of these two extremes (6).Structural evidence for respiratory-chain supercomplexes, initiated by observations by blue native PAGE analyses of mammalian mitochondria (4, 7), has culminated in electron microscopy data that revealed the arrangement of complexes I, III, and IV in a particular class of isolated supercomplex assembly (8, 9); respiratory-chain supercomplexes have also been observed (at lower resolution) in the membrane (10...

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A stabilizing factor for mitochondrial respiratory supercomplex assembly regulates energy metabolism in muscle

Cited by 138 publications

References 52 publications

Placental mitochondrial content and function in intrauterine growth restriction and preeclampsia

Placental mitochondrial content and function in intrauterine growth restriction and preeclampsia

Deficiency of PHB complex impairs respiratory supercomplex formation and activates mitochondrial flashes

Kinetic evidence against partitioning of the ubiquinone pool and the catalytic relevance of respiratory-chain supercomplexes

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